Review Clinical review: Fever in intensive care unit patients Michael Ryan1 and Mitchell M Levy2 1Fellow, Brown Medical School/Rhode Island Hospital, Pulmonary/Critical Care Division, Pr
Trang 1COX-2 = cyclooxygenase-2; HSF = heat shock factor; HSP = heat shock protein; ICU = intensive care unit; IL = interleukin; NF = nuclear factor; OVLT = organum vasculosum of the laminae terminalis; TNF-α = tumor necrosis factor alpha
Fever occurs commonly in hospitalized patients It is estimated
that nosocomial fevers occur in approximately one-third of all
medical patients at some time during their hospital stay [1] In
patients admitted to the intensive care unit (ICU) with severe
sepsis, the incidence of fever is more than 90% [2] As there
is variation in the incidence of reported fevers, the etiology of
fever in critically ill patients is similarly diverse—both infectious
and noninfectious etiologies are common [1,3,4]
The definition of fever is arbitrary The mean body
tempera-ture (oral) in healthy individuals is approximately 36.8°C
(98.2°F), with a range of 35.6°C (96°F) to 38.2°C (100.8°F)
and a slight diurnal variation [5] The Society of Critical Care
Medicine and the Infectious Disease Society of America, in a
recent consensus statement, suggested that a temperature of
above 38.3°C (101°F) should be considered a fever and
should prompt a clinical assessment [4]
Physician and staff response to fever varies institutionally
Besides evaluating the patient and initiating a workup
based on the clinical evaluation, it is common for the patient to receive either pharmacologic or mechanical antipyretic therapy However, there is little evidence that would support such routine practice The traditional view,
at least in pediatrics, is that an exuberant febrile response
is inherently dangerous and can, in the worse case, lead to seizures and brain damage [6] Adult nonhealthcare workers (i.e patient family members) also have significant misconceptions regarding the perceived detrimental effects of fever [7] In this complicated psychosocial setting, it is easy for the physician to merely treat the fever However, there are costs associated with such therapies It
is estimated that when either paracetamol, icepacks or cooling blankets are used, it can cost one 18-bed ICU between $10,000 and $29,000 per year [8] Pharmacolog-ical means to reduce fever cause renal and hepatic dys-function in patients who are volume depleted or who have underlying kidney or liver disease [9] Additionally, there is evidence, at least in animal models, that fever is a benefi-cial host response to infection [10–12]
Review
Clinical review: Fever in intensive care unit patients
Michael Ryan1 and Mitchell M Levy2
1Fellow, Brown Medical School/Rhode Island Hospital, Pulmonary/Critical Care Division, Providence, Rhode Island, USA
2Associate Professor, Brown Medical School/Rhode Island Hospital and Medical Director of MICU, Rhode Island Hospital, Pulmonary/Critical Care
Division, Providence, Rhode Island, USA
Correspondence: Mitchell M Levy, mitchell.levy@brown.edu
Published online: 8 March 2003 Critical Care 2003, 7:221-225 (DOI 10.1186/cc1879)
This article is online at http://ccforum.com/content/7/3/221
© 2003 BioMed Central Ltd (Print ISSN 1364-8535; Online ISSN 1466-609X)
Abstract
Fever is a common response to sepsis in critically ill patients Fever occurs when either exogenous or
endogenous pyrogens affect the synthesis of prostaglandin E2in the pre-optic nucleus Prostaglandin
E2slows the rate of firing of warm sensitive neurons and results in increased body temperature The
febrile response is well preserved across the animal kingdom, and experimental evidence suggests it
may be a beneficial response to infection Fever, however, is commonly treated in critically ill patients,
usually with antipyretics, without good data to support such a practice Fever induces the production
of heat shock proteins (HSPs), a class of proteins critical for cellular survival during stress HSPs act
as molecular chaperones, and new data suggest they may also have an anti-inflammatory role HSPs
and the heat shock response appear to inhibit the activation of NF-κβ, thus decreasing the levels of
proinflammatory cytokines The anti-inflammatory effects of HSPs, coupled with improved survival of
animal models with fever and infection, call into question the routine practice of treating fever in
critically ill patients
Keywords fever, heat shock proteins, intensive care unit, nuclear factor-κB, sepsis
Trang 2The goal of the present review is to question, by critically
evaluating the literature, the practice of routinely treating fever
in the ICU patient The pathophysiology of fever will be
reviewed, the animal and human data that have evaluated the
role and the potential beneficial effects of fever in disease
states will be examined, and the hemodynamic and metabolic
costs of fever will be summarized
The physiology of fever
Fever is extremely well preserved throughout evolution It has
been found in numerous phyla and is estimated to be more
than four million years old [13] Fever is seen in mammals,
reptiles, amphibians, and fish as well as in some
inverte-brates Not only is it found in endothermic (warm-blooded)
animals, it is also seen in ectothermic (cold-blooded) animals
[11] In response to infection, lizards will elevate their body
temperature by selecting a warmer microclimate [14] The
febrile response, defined by Plaisance and Mackowiak, is a
“complex physiologic reaction to disease involving a cytokine
mediated rise in core temperature, generation of acute-phase
reactants, and activation of numerous physiologic
endocrino-logic and immunoendocrino-logic systems” [15]
Exogenous stimuli, such as endotoxin, staphylococcal
erytho-toxin and viruses, induce white blood cells to produce
endogenous pyrogens The most potent of these
endo-genous pyrogens are IL-1 and tumor necrosis factor alpha
(TNF-α) [16] Other endogenous pyrogens that are integral in
the febrile response include IL-6 and the interferons [17]
These endogenous pyrogens act on the central nervous
system at the level of the organum vasculosum of the laminae
terminalis (OVLT) The OVLT is surrounded by the medial and
lateral portions of the pre-optic nucleus, the anterior
hypo-thalamus and the septum pallusolum [18]
The exact mechanism of how circulating cytokines in the
systemic circulation effect neural tissue remains unclear It
has been hypothesized that a leak in the blood–brain barrier
at the level of the OVLT allows the central nervous system to
sense the presence of endogenous pyrogens Additional
pro-posed mechanisms include active transport of cytokines into
the OVLT or activation of cytokine receptors in endothelial
cells of the neural vasculature, which than transduce signals
to the brain [19]
The OVLT synthesizes prostaglandin, especially
prosta-glandin E2, in response to endogenous pyrogens
Prosta-glandin E2acts directly on the cells of the pre-optic nucleus
to reduce the rate of firing of warm sensitive neurons, and it is
one of the downstream products of the arachidonic acid
pathway [20,21] There is ample evidence that
cyclooxyge-nase-2 (COX-2) in neural vasculature is important in the
for-mation of fever Induction of the febrile response by
lipopolysaccharide, TNF-α, and IL-1β resulted in increased
COX-2 mRNA in the cerebral vasculature of numerous
exper-imental models of fever [22] In a murine model COX-2
knockout mice were unable to mount a febrile response to endotoxin, and in humans COX-2 selective inhibitors were shown to reduce fever [23,24] In fact, over 30 years ago, the NSAIDS were shown to inhibit the action of COX-2 [25] Shortly afterwards, a similar mechanism was discovered for acetaminophen, but this effect was only found in neural
COX-2 enzymes; thus explaining why acetaminophen is a strong anti-pyretic but devoid of anti-inflammatory effects [26]
Fever and clinical outcomes
Although the febrile response has existed for millions of years, controlled studies evaluating the benefits of fever do not exist Most of the studies in humans evaluating clinical outcomes, fever and infection have been case–control series For example, in the pre-antibiotic era, artificial fever was used, with limited success and without controlled trials, to treat neurosyphilis [27,28] Evaluation of fever in animal models is confounded by the fact that stressed animals often increase their body temperature several degrees with handling and is confounded by questions about the appropriate pyrogenic stimulus in a particular species [11] It has been postulated that a behavior so widely preserved, yet metabolically expen-sive, must convey some net benefit to the host or it would not have been retained during evolution [11]
In vitro and animal data evaluating the effect of temperature
on survival during infection suggest that fever may be benefi-cial to the host Increased survival with fever has been demonstrated in animal studies [29,30] In fact, the majority
of studies (14 out of 21 studies) evaluated in one review demonstrated a deleterious effect of lowering body tempera-ture [11] Additionally, increasing temperatempera-ture has effects on the minimum inhibitory concentration of antibiotics to bacte-ria As the experimental temperature increased past 38.5°C, the authors of one study found reductions in the minimum inhibitory concentrations, representing a progressive increase
in the antimicrobial activity of antibiotics [31]
While in vitro data and animal data seems to suggest that
treatment of fever does not favorably impact morbidity and mortality, human studies in this area are lacking In a study with 218 patients who had gram-negative bacteremia, fever correlated positively with survival [32] However, this data is confounded by the fact that the majority of afebrile septic patients who died did not receive appropriate antibiotic therapy Additionally, another retrospective case series showed that failure to mount a febrile response within the first
24 hours was associated with increased mortality [33] When patient comfort was evaluated as a primary outcome variable, there was no difference in the comfort level of patient who had fever treated versus control [8]
Fever and the immune response
Increased temperature is known to induce changes in many
of the effector cells of the immune response In addition to these changes, fever induces the heat shock response The
Trang 3heat shock response is a complex reaction to fever, to
cytokines, or to numerous other stimuli The end result of this
reaction is production of heat shock proteins (HSPs), a class of
proteins crucial to cellular survival [34] Ritossa first reported
the heat shock response in 1962 when he noticed changes in
the Drosphilia chromosome in response to increased
tempera-ture [35] The protein products of these chromosomal changes
were subsequently isolated and called HSPs [36]
The heat shock response provides a cell or organism with
ther-motolerance When a cell is subjected to a sublethal heat
stress, this sublethal stress protects the organism from a
sub-sequent potentially lethal heat stress [37] This response
seems to not only function to provide protection from heat, but
can, by a mechanism called cross-tolerance, be induced by a
particular stressor (e.g heat) and can protect against cell death
from an entirely different lethal stress (e.g endotoxin) [34]
HSPs have subsequently been found in numerous organisms,
and the DNA sequencing and subsequent protein structure is
highly preserved between organisms [38] Because they are
so well preserved throughout nature, it is postulated that
HSPs are critical for cell survival They are molecular
chaper-ones that escort proteins marked for translocation throughout
the organelles of a cell, they participate in refolding proteins
that have become denatured during cellular stress, and they
transport severely damaged proteins to proteolytic organelles
for destruction [39] Additionally, HSPs also are important in
the apoptotic response, modulating the immune response,
and in regulating steroid hormone receptors
Inducible HSPs exist in the cytosol, bound to proteins called
heat shock factors (HSFs) [34] A stress causes HSPs to
dis-sociate from HSFs, and the HSFs are then phosphorylated
These phosphorylated HSFs form a trimer that enters the
nucleus of the cell and, after further phosphorylation, bind to
the cellular DNA on a sequence called a heat shock element
The heat shock element is a promoter sequence for the HSP
Binding of the HSF to the heat shock element causes
tran-scription of HSP mRNA Translation of the mRNA occurs,
and further HSPs are produced [39]
This system is regulated on several levels HSPs bind to
dis-sociated HSFs in the cytosol, preventing the formation of
further HSF trimers to act as DNA promoters Additionally,
there is evidence of post-transcriptional regulation of HSP
production [34] In vitro experiments show that while HSP
mRNA is increased secondary to a stressor, the amount of
HSPs produced is variable and is dependent on the
magni-tude of the stressor [40]
Heat shock response: clinical implications in
sepsis
The importance of the heat shock response in vivo has been
demonstrated in numerous experiments Ryan and colleagues
heated rats from 39°C to 42.5°C and then, 24 hours later,
administered a lethal dose of endotoxin to the animals [10] The mortality in the control group at 48 hours was 71.4%, while no rats died in the heat-treated group Villar and col-leagues showed that, during intra-abdominal sepsis, previous heat treatment significantly impacted mortality and reduced organ injury [12] In this study, rats underwent heat treatment
18 hours before cecal ligation and puncture Survival at
7 days was noted, and rats were sacrificed at various times after the cecal ligation and puncture to examine the organ his-tology The HSP-72 levels increased in the lungs and the heart of heat-treated animals shortly after heat treatment Animals that underwent cecal ligation and puncture without previous heat treatment had no detectable expression of HSP-72 at any time in the course of their illness The heat-treated rats had improved mortality, had less organ damage, and had less evidence of acute lung injury
Interestingly, severe sepsis may be associated with a dimin-ished heat shock response Lymphocytes obtained from a group of patients with severe sepsis were compared with lym-phocytes obtained from critically ill postoperative patients and healthy volunteers [41] At baseline, all three groups had similar percentages of lymphocytes expressing HSP-70 When the lymphocytes were given an endotoxin challenge, however, the percentage of lymphocytes that expressed HSP-70 was signifi-cantly less in the septic group If patients recovered from severe sepsis, there was an increase in the percentage of their lymphocytes that produced HSP-70 to endotoxin challenge This may suggest that HSPs modulate the septic response
There is strong evidence that HSPs have anti-inflammatory
roles In vitro studies have shown that the heat shock
response reduces levels of TNF-α, IL-1, IL-6, and IL-10 [42] This effect is not isolated to cell cultures, as it has also been demonstrated in murine models of sepsis [43,44] The ability
of the heat shock response to inhibit a wide array of inflam-matory mediators implies that it must modulate the septic response at one or more key regulatory steps Indeed, recent data has demonstrated that induction of the heat shock response downregulates the activity of NF-κB
Heat shock response and NF- κκB
NF-κB is a nuclear transcription factor that, when activated, binds to DNA promoter regions that encode for the mRNA of numerous inflammatory molecules The effect of this binding
is to enhance the expression of these inflammatory mediators [45] NF-κB, therefore, is a potent upstream modulator of the proinflammatory response NF-κB is a dimer composed of two proteins from the ReL family It is contained in the cytosol
of the cell, bound to an inhibitory protein called I-κB During the process of NF-κB activation, I-κB is phosphorylated by a kinase called IKK [38] This causes the I-κB to dissociate from NF-κB, uncovering the nuclear translocation signal on the NF-κB dimer Unbound NF-κB is than able to serve its role as a DNA promoter to enhance the transcription of mRNA, which codes for the inflammatory molecules
Trang 4NF-κB activity has been reported to correlate with mortality in
septic shock patients Borher and colleagues followed daily
NF-κB activity obtained from nuclear extracts of peripheral
blood monocytes They found that survivors of septic shock,
when compared with patients who died, had significantly less
increases in their daily NF-κB activity In fact, all five patients
who died had a doubling of their baseline NF-κB activity [46]
In a similar study, Paterson and colleagues showed that there
was increased nuclear activity of NF-κB in both monocytes
and neutrophils of septic patients when compared with
healthy controls [47] The patients who died from sepsis had
increased levels of NF-κB activity in the nucleus of
mono-cytes, as compared with patients who survived sepsis
The exact mechanism by which hyperthermia, via induction of
the heat shock response, appears to modulate the immune
response to sepsis is thought to be through inhibition of IKK
proteins [45] As mentioned earlier, IKK has been shown to
be an important regulator of NF-κB activity This protein
phos-phorylates I-κB and allows the regulatory protein to
disassoci-ate from NF-κB, thus allowing NF-κB to migrate into the
nucleus of the cell [38,45] Inhibition of IKK will therefore lead
to decreased NF-κB activation and, ultimately, to less
down-stream proinflammatory cytokine gene expression
After induction of the heat shock response with TNF-α,
human respiratory and alveolar cells had less production of
inflammatory cytokines, had less phosphorylated I-κB, had
higher total levels of I-κB, and had less IKK activity [48]
Addi-tionally, recent in vitro experiments in human endothelial cells
have duplicated this work, showing that the heat shock
response reduces the activation of IKK, thereby reducing the
phosphorylation of the inhibitory protein I-κB and preventing
activation of NF-κB [49]
These data, which link fever and heat shock response to
inhi-bition of NF-κB, and thus decreased downstream cytokine
production, raise an important question about the wisdom of
treating hypothermia in septic patients
Summary
Fever in the ICU, and especially in patients with sepsis, is
extremely common It occurs from activity of endogenous
pyrogens that enhance prostaglandin E2 production in the
pre-optic region of the hypothalamus Drugs that inhibit
COX-2, as well as measures that promote active cooling, are
effective at suppressing fever and are frequently used during
critically illness Despite their widespread use, there is data
that suggest fever is beneficial to animals with infection, and
there is no evidence that treating fever changes mortality
There is theoretical benefit that, through the heat shock
response and subsequent reduction of NF-κB, fever may play
a protective role in the survival of patients with severe sepsis
In the absence of meaningful evidence for the beneficial
effects of fever reduction, the commonplace reduction of
fever in critically ill patients must be called into question
Competing interests
None declared
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